Hypertension, a disease or a collection of diseased states, is manifested in chronically high blood pressure. There is no known cause or single mechanism which exists to explain the cellular and molecular basis of the majority of cases of hypertension. This may in part be due to the extreme difficulty in dissociating the cause and effects of high blood pressure from the genetic expression of hypertension. Investigation in our laboratory has resulted in the development of a cellular in vitro system from the brains of normotensive and genetically hypertensive rats in which the expression of various physiological events can be investigated without confounding effect of blood pressure. These studies have demonstrated the existence of a negative feedback interaction between angiotensin II (Ang II) receptor expression and the catecholamine (CA) system in normotensive neurons. In contrast, neurons from SH rat brains lack such a negative feedback interaction. The objective of our present investigation will be to further elucidate the cellular mechanisms of the regulation of Ang II and adrenergic systems in both strains of rats, to establish a working hypothesis from these in vitro experiments and then to test its validity with in vivo experimentation. Specifically, the mechanism of Ang II synthesis and release and the involvement of adrenergic receptors in this release by neurons of normotensive and SH rats will be studied. In addition, the turnover, coupling and regulation of alpha 1-adrenergic receptors in both normotensive and hypertensive neurons will be investigated. The knowledge gathered from the cell culture studies will be tested and validated with experiments on the cardioregulatory brain areas of the adult normotensive and hypertensive animals. For example, the negative feedback interaction hypothesis will be tested to determine its role in the regulation of blood pressure. It is anticipated that such in vitro and in vivo approaches will provide a unique understanding of the cellular mechanisms of central Ang II-CA interactions. This may influence tremendously the way we presently look at and treat hypertension and thus may lead to new strategies for its management and ultimately its prevention.